Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study

BACKGROUND The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear. METHODS This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m$^{2}$ per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m$^{2}$ temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990. FINDINGS Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported. INTERPRETATION Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status. FUNDING Merck Sharpe & Dohme

Distinct MRI pattern of "pseudoresponse" in recurrent glioblastoma multiforme treated with regorafenib: Case report and literature review

: Antiangiogenic agents can induce a distinct MRI pattern in glioblastoma, characterized by a decrease in the contrast enhancement on T1-weighted images and a simultaneous hyperintensity on T2-weighted or fluid-attenuated inversion recovery images

Phase II Randomized Study of Vandetanib Plus Gemcitabine or Gemcitabine Plus Placebo as First-Line Treatment of Advanced Non–Small-Cell Lung Cancer in Elderly Patients

Introduction:The aim of the present study was to evaluate the efficacy and tolerability of vandetanib plus gemcitabine (V/G) compared with gemcitabine alone in elderly patients with untreated advanced non–small-cell lung cancer.Methods:This was a phase II, randomized, double-blind study. A total of 124 elderly patients (mean age, 75 yr; age range, 70–84 yr; 73% men) received V/G (n = 61) or placebo plus gemcitabine (n = 63). Progression-free survival (PFS) was the primary endpoint. Secondary endpoints were overall survival, objective response rate, duration of response, disease control rate, time to deterioration of performance status, and safety outcomes.Results:PFS was significantly prolonged with V/G (median, 183 days; 95% confidence interval, 116–214) compared with placebo plus gemcitabine (median, 169 days; 95% confidence interval, 95–194; p = 0.047). No statistically significant differences between arms were observed in all secondary endpoints, including overall survival. The addition of vandetanib to gemcitabine was well tolerated. The rate of patients with ≥1 treatment-related adverse event was comparable in the two arms, pyrexia, dyspnea, and neutropenia being the most common adverse events.Conclusions:V/G combination was associated with a statistically significant prolongation of PFS compared with gemcitabine alone in untreated elderly patients with advanced non–small-cell lung cancer, with an acceptable safety profile

Molecular Targeted Therapies: Time for a Paradigm Shift in Medulloblastoma Treatment?

Medulloblastoma is a rare malignancy of the posterior cranial fossa. Although until now considered a single disease, according to the current WHO classification, it is a heterogeneous tumor that comprises multiple molecularly defined subgroups, with distinct gene expression profiles, pathogenetic driver alterations, clinical behaviors and age at onset. Adult medulloblastoma, in particular, is considered a rarer “orphan” entity in neuro-oncology practice because while treatments have progressively evolved for the pediatric population, no practice-changing prospective, randomized clinical trials have been performed in adults. In this scenario, the toughest challenge is to transfer the advances in cancer genomics into new molecularly targeted therapeutics, to improve the prognosis of this neoplasm and the treatment-related toxicities. Herein, we focus on the recent advances in targeted therapy of medulloblastoma based on the new and deeper knowledge of disease biology

Glioblastoma: Emerging Treatments and Novel Trial Designs

Management of glioblastoma is a clinical challenge since very few systemic treatments have shown clinical efficacy in recurrent disease. Thanks to an increased knowledge of the biological and molecular mechanisms related to disease progression and growth, promising novel treatment strategies are emerging. The expanding availability of innovative compounds requires the design of a new generation of clinical trials, testing experimental compounds in a short time and tailoring the sample cohort based on molecular and clinical behaviors. In this review, we focused our attention on the assessment of promising novel treatment approaches, discussing novel trial design and possible future fields of development in this setting

Discovering the Molecular Landscape of Meningioma: The Struggle to Find New Therapeutic Targets

Meningiomas are the most common primary CNS tumors. They are usually benign but can present aggressive behavior in about 20% of cases. The genetic landscape of meningioma is characterized by the presence (in about 60% of cases) or absence of NF2 mutation. Low-grade meningiomas can also present other genetic alterations, particularly affecting SMO, TRAF7, KLF4 AKT1 and PI3KCA. In higher grade meningiomas, mutations of TERT promoter and deletion of CDKN2A/B seem to have a prognostic value. Furthermore, other genetic alterations have been identified, such as BAP1, DMD and PBRM1. Different subgroups of DNA methylation appear to be correlated with prognosis. In this review, we explored the genetic landscape of meningiomas and the possible therapeutic implications

Clinical efficacy of immune checkpoint inhibitors in patients with brain metastases

Brain metastases (BMs) represent a negative prognostic factor for patients with solid malignancies. BMs are generally approached with loco-regional treatments and the blood-brain barrier limits the efficacy of some systemic drugs. The aim of this review is to summarize current knowledge about the role of immune checkpoint inhibitors for the management of brain metastases in patients with solid malignancies. We performed a review of available literature. Immune checkpoint inhibitors represent the standard treatment for several advanced solid malignancies. However, with the exception of melanoma their clinical role in other solid malignancies is not completely clear due to the exclusion of patients with BM from approval clinical trials. Immune-checkpoint inhibitors may be an effective treatment of brain metastases of melanoma while their clinical role on brain metastases from other solid malignancies is uncertain

Expertise is crucial to prolong survival in average risk medulloblastoma: long-term results of a retrospective study

Purpose: Medulloblastoma is a rare tumor in adults and the use of adjuvant chemotherapy in average risk patients is debated. Methods: Patients included in our study were &gt; 16 years of age, had histologically confirmed medulloblastoma, and underwent adjuvant radiotherapy with or without chemotherapy. Average risk was defined according to the Chang classification. Results: We included 48 average-risk patients. Median follow-up was 151.5 months (95% confidence interval, 124.5-178.5). Both progression-free survival (PFS) and overall survival (OS) were significantly influenced by adjuvant chemotherapy (PFS: hazard ratio [HR], 0.334, p = 0.05; OS: HR, 0.187, p = 0.017) and by receiving the treatment in a referral center (PFS: HR, 0.250, p = 0.008; OS: HR, 0.295, p = 0.038). Conclusions: Treating patients with average-risk medulloblastoma in a referral center improves both PFS and OS, does adding adjuvant chemotherapy

IDH1 Non-Canonical Mutations and Survival in Patients with Glioma

Background: Non-canonical mutations of the isocitrate dehydrogenase (IDH) genes have been described in about 20–25% and 5–12% of patients with WHO grade II and III gliomas, respectively. To date, the prognostic value of these rare mutations is still a topic of debate. Methods: We selected patients with WHO grade II and III gliomas and IDH1 mutations with available tissue samples for next-generation sequencing. The clinical outcomes and baseline behaviors of patients with canonical IDH1 R132H and non-canonical IDH1 mutations were compared. Results: We evaluated 433 patients harboring IDH1 mutations. Three hundred and ninety patients (90.1%) had a canonical IDH1 R132H mutation while 43 patients (9.9%) had a non-canonical IDH1 mutation. Compared to those with the IDH1 canonical mutation, patients with non-canonical mutations were younger (p p = 0.017). Multivariate analysis confirmed that the extension of surgery (p = 0.003), the presence of the 1p19q codeletion (p = 0.001), and the presence of a non-canonical mutation (p = 0.041) were variables correlated with improved overall survival. Conclusion: the presence of non-canonical IDH1 mutations could be associated with improved survival among patients with IDH1 mutated grade II–III glioma

miR-196B-5P and miR-200B-3P Are Differentially Expressed in Medulloblastomas of Adults and Children

Medulloblastoma is a highly aggressive brain tumor that typically affects children, while in adults it represents ~1% of all brain tumors. Little is known about microRNA expression profile of the rare adult medulloblastoma. The main aim of this study was to identify peculiar differences in microRNA expression between childhood and adult medulloblastoma. Medulloblastomas were profiled for microRNA expression using the Exiqon Human miRNome panel (I + II) analyzing 752 microRNAs in a training set of six adult and six childhood cases. Then, the most differentially expressed microRNAs were validated in a total of 21 adult and 19 childhood cases. Eight microRNAs (miR-196b-5p, miR-183-5p, miR-200b-3p, miR-196a-5p, miR-193a-3p, miR-29c-3p, miR-33b-5p, and miR-200a-3p) were differentially expressed in medulloblastoma of adults and children. Analysis of the validation set confirmed that miR-196b-5p and miR-200b-3p were significantly overexpressed in medulloblastoma of adults as compared with those of children. We followed an in silico approach to investigate direct targets and the pathways involved for the two microRNAs (miR-196b and miR-200b) differently expressed between adult and childhood medulloblastoma. Adult and childhood medulloblastoma have different miRNA expression profiles. In particular, the differential dysregulation of miR-196b-5p and miR-200b-3p characterizes the miRNA profile of adult medulloblastoma and suggests potential targets for novel diagnostic, prognostic, or therapeutic strategies